Endogenous steroidal androgens exert profound influences on a multitude of physiological functions. The effects of steroidal androgens (e.g. testosterone and 5α-dihydrotestosterone (DHT)) are mediated by the androgen receptor (AR) and may be characterized as anabolic or androgenic in nature. Following androgen binding, the AR undergoes a conformational change then translocates to the cell nucleus where it binds to specific DNA sequences termed androgen response elements (AREs) to initiate or repress transcription of target genes. Anabolic (i.e. tissue building) effects of androgens include increasing muscle mass and strength and bone mass, whereas androgenic (i.e. masculinizing) effects include the development of male secondary sexual characteristics such as the internal reproductive tissues (i.e. prostate and seminal vesicle), the external genetalia (penis and scrotum), libido, and hair growth patterns.
Reductions in androgen levels as may occur with aging are associated with serious effects in both males and females. For example, as men age and testosterone levels decline, bones weaken, diabetes and cardiovascular disease rates increase, and the ratio of muscle mass to fat decreases. In females, low plasma levels of circulating testosterone are associated with diminished libido, unexplained fatigue, general lack of well being, and a loss of bone mineral density in post menopausal women. Clinically, the principal application of androgen therapy has been in the treatment of hypogonadism in men. Significantly, androgen replacement therapy in hypogonadal men has also been shown to decrease bone resorption and increase bone mass. Other indications for which androgens have been used clinically include treatment of delayed puberty in boys, anemia, primary osteoporosis, and muscle wasting diseases. In addition, androgen replacement therapy has been used recently in aging men and for the regulation of male fertility. In females, androgen therapy has been used clinically for the treatment of sexual dysfunction or diminished libido.
However, androgen therapy has limitations. For example, unwanted side effects of steroidal androgen therapy include growth stimulation of the prostate and seminal vesicles. In addition, stimulation of prostate tumors and elevations in prostate specific antigen (PSA) (an indication of increased prostate cancer risk), have been associated with androgen use. Furthermore, preparations of unmodified and modified steroidal androgens have been found to suffer from rapid degradation in the liver leading to poor oral bioavailability and short duration of activity following parenteral administration, variations in plasma levels, hepatotoxicity, or cross reactivity with other steroid hormone receptors (e.g. the glucocorticoid receptor (GR), the mineralocorticoid receptor (MR), and the progesterone receptor (PR)). Furthermore, in females, the use of steroidal androgens may lead to hirsutism or virilization.
Thus, there remains a need in the art for alternatives to steroidal androgen therapy which possess the beneficial pharmacological properties of steroidal androgens, but with a reduced likelihood or incidence of the typical limitations associated with steroidal androgen therapy. Recent efforts to identify suitable replacements for steroidal androgens have focused on identifying tissue selective androgen receptor modulators (SARMs) which display a differentiated profile of activity in androgenic tissues. In particular, such agents preferably display androgen agonist activity in anabolic tissues such as muscle or bone, yet are only partial agonists or even antagonists in other androgenic tissues such as the prostate or seminal vesicles.
Thus, it is an object of the present invention to provide nonsteroidal AR ligands which possess androgen agonist activity. More particularly, it is an object to provide nonsteroidal androgen agonists which bind to AR with greater affinity relative to the other steroid hormone receptors. Even more particularly, it is an object to provide tissue selective androgen receptor modulators (SARMs) which display androgen agonist activity in muscle or bone, but only partial agonist, partial antagonist or antagonist activity in androgenic tissues such as the prostate or seminal vesicle.
The following references provide examples of the current state of the art as it relates to the present invention:
Brown, Endocrinology (2004); 145(12): 5417-5419 provides a review of nonsteroidal selective androgen receptor modulators.
Cadilla et al., Curr. Top. Med. Chem (2006); 6(3): 245-270 provides a review of androgen receptor modulators.
Segal et al., Expert Opin. Investig. Drugs (2006); 15(4); 377-387 provides a review of androgen receptor modulators.
Co-pending International Application PCT/US2006/024122 discloses tetrahydrocarbazole compounds as androgen receptor modulators.